Vancomycin is represented by the following Chemical Formula I and is produced by Actinomycetes microorganisms, i.e., Amycolatopsis orienatalis (ATCC 19795) strains. Vancomycin is also prepared by chemical bonding of —O-vancosamin- —O-glucosyl with a heptapeptide. In addition, vancomycin is a glycopeptide-type antibiotic having a molecular weight of about 1449, and realizes antibiotic activity by the mechanism in which it is bound to a mucopeptide precursor terminated with D-ala-D-ala to inhibit cell wall synthesis. Generally, vancomycin shows an excellent pharmacological effect against gram-positive bacteria, such as Streptococci, Staphylococci and Clostridium difficile, and penicillin- or cephalosporin antibiotic-resistant gram-positive bacteria.

In addition, it is known that vancomycin is highly effective in the treatment against methicillin-resistant staphylococcus aureus (MRSA) fatal to patients subjected to surgery, old-aged patients and persons with weak immunity. Such vancomycin salts, particularly, vancomycin hydrochloride has been currently used as oral (liquid or capsules) or injection formulations.
Various technological processes for separating and purifying vancomycin have been known to date, and typical examples thereof are as follows:
U.S. Pat. No. 7,018,814 and Korean Patent No. 554481 disclose a method for purifying vancomycin hydrochloride, including: (a) passing a microorganism-fermented solution containing vancomycin through a strong acidic cation exchange resin under the condition of pH 1-3 by using, as an eluent, an aqueous ammonium hydroxide solution having a concentration of 0.05-0.2N and a pH of 9-11; (b) adjusting the resultant solution to a pH of 3-5 and passing it continuously through a weak basic anion exchange resin and alumina, followed by washing with water, to remove the pigments; (c) passing the resultant solution through a hydrophobic adsorption resin by using, as an eluent, an aqueous C1-C4 alcohol solution; and (d) adding hydrochloric acid to the resultant solution to adjust the pH to 2-5, and adding a water-soluble organic solvent containing a C1-C4 alcohol, acetonitrile, acetone or methyl isobutyl ketone to perform crystallization of vancomycin hydrochloride.
According to the above patents, it is said that crystal bodies are obtained through the crystallization step during the separation and purification of the vancomycin-containing microorganism-fermented solution, the crystal bodies are filtered, and the filtered precipitate (crystal bodies) are subjected to vacuum drying (vacuum drying at a temperature of 40° C. or lower in examples) in order to obtain vancomycin hydrochloride.
U.S. Pat. No. 5,853,720 discloses a process for purifying vancomycin, including subjecting a microorganism-fermented solution to preparative chromatography using a silica column, and carrying out precipitation by using ethanol from a salt-water-ethanol solution. According to the above patent, a main fraction (average purity: 93%) and a side fraction (purity of 90% or less) are obtained from the silica gel column after the cultivation-precision filtration-adsorption using an ion exchange resin. In the case of the main fraction, concentration-filtration-concentration and discoloration are performed, and then high-temperature spray drying (air inlet temperature: 115-130° C., air outlet temperature: 85±5° C.)—vacuum drying (45-50° C.) are carried out to obtain a dried solid product. On the other hand, in the case of the side fraction, desalting and concentration using a reverse osmosis process after acidification—precipitation (crystallization) using ethanol after adding ethanol and sodium chloride—cooling and filtration are carried out, and then the resultant product is resent to the silica gel column to perform the treatment for the main fraction. In the case of the above purification process, a relatively large number of steps (at least 7 to 11 steps) are included. Although the above patent describes about the purity of vancomycin (salt) obtained after the treatment with the silica gel column, there is no description about a change in purity after the subsequent steps (particularly, reverse osmosis filtration step and vacuum drying step). As described hereinafter, although vancomycin with a purity of 93% or higher can be obtained by the above process, the purity decreases in the subsequent drying steps (particularly, high-temperature spray drying and vacuum drying at 45-50° C.), thereby making it difficult to obtain a product having a purity satisfying the criteria defined by European Pharmaceutical Standards, i.e., a purity of 93% or higher.
However, the above-mentioned processes according to the related art cause such problems as degradation of purity of at least 3.2% and at most 5.6% for 1-2 days of vacuum drying and degradation of stability of vancomycin. In addition, when the vacuum drying step is performed at a decreased temperature of 25° C. for the same period of time, it is shown that a change in purity is merely less than 1%, however, the resultant product contains impurities including at least 0.5% of ethanol and up to 4-10% of moisture.
As described above, vancomycin is a temperature-sensitive medicine, and thus a vacuum drying temperature of 40-50° C. cannot ensure the stability in terms of purity. On the other hand, a vacuum drying temperature decreased to 40° C. or less cannot satisfy the standards of ethanol content and moisture content. Therefore, such vacuum drying adopted as the final step for providing a dried product in the conventional purification processes is not suitable for the efficient production of stable high-purity vancomycin. Moreover, the above patents according to the related art are focused on the separation and purification processes, and there is no particular description about the problems of degradation of stability and purity caused by the drying step.
Meanwhile, according to the European Pharmaceutical Standards (European Pharmacopoeia 6.0), particularly for stable high-purity vancomycin, it is required for vancomycin to have a purity of 93% or higher and a moisture content of at most 5%. It is also required for vancomycin to have an ethanol content less than about 0.5% with reference to ICH Harmonised tripartite guideline (Impurities: Guideline for Residual Solvents). Under these circumstances, there is an imminent need for developing a process for purifying vancomycin, which prevents a drop in purity caused by poor temperature stability and satisfies various standards related to medicines.